The purpose of this study is to investigate tomosynthesis mammography to improve the sensitivity and specificity of breast cancer detection. By removing overlapping tissue, this system can allow detection of obscured lesions and permit better 3D characterization of lesions. The specific aims of the proposed study are to: (1) Optimize tomosynthesis technique using specimen and patient images. (2) Implement soft-copy display system for tomosynthesis images and CAD outputs to maximize radiologist productivity and performance. (3) Perform prospective pilot studies to evaluate radiologist performance with breast tomosynthesis. (4) Investigate CAD of breast masses as an integral component of breast tomosynthesis. In preliminary studies, we evaluated the physical characteristics of an investigational digital mammography system modified for tomosynthesis scanning, and optimized the radiographic technique for tomosynthesis. We translated our experience with chest tomosynthesis into mammography, and demonstrated feasibility of our reconstruction algorithm on phantoms, mastectomy specimens, and patients. We developed novel CAD algorithms for the detection of breast masses in mammography, and will parlay that experience into the 3D tomosynthesis data. This proposal presents a complete plan to demonstrate physical and clinical feasibility. Upon the successful completion of each aim, the immediate benefit will be crucial information which will facilitate commercial translation of this breast tomosynthesis system by our industrial partner, as well as the evaluation of similar systems from other academic groups and manufacturers.